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Purpose To describe the rationale and methods for a prospective, open-cohort study assessing the long-term safety of Prolia® for treatment of postmenopausal osteoporosis (PMO) in postmarketing settings. Methods Data will be derived from United States Medicare, United Healthcare, and Nordic (Denmark, Sweden, Norway) national registries. Observation will begin on the date of first Prolia® regulatory approval (May 26, 2010) and continue for 10 years. Women with PMO will be identified by postmenopausal age, osteoporosis diagnosis, osteoporotic fracture, or osteoporosis treatment. Exposure to Prolia® and bisphosphonates will be updated during follow-up; exposure cohorts will be defined based on patient-years during which patients are on- or post-treatment. Nine adverse events (AEs) will be assessed based on diagnosis codes: osteonecrosis of the jaw (ONJ), atypical femoral fracture (AFF), fracture healing complications, hypocalcemia, infection, dermatologic AEs, acute pancreatitis, hypersensitivity, and new primary malignancy. Medical review will confirm selected potential cases of ONJ and AFF. Incidence rates (IRs) of AEs will be described overall and for exposure cohorts; multivariate Cox proportional hazard regression models will compare IRs of AEs across exposure cohorts. Utilization patterns of Prolia® for approved, and unapproved indications will be described. Conclusion This study is based on comprehensive preliminary research and considers methodological challenges specific to the study population. The integrated data systems used in this regulatory committed program can serve as a powerful data resource to assess diverse and rare AEs over time. © 2013 Amgen Inc. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons, Ltd.

The incidences of osteoporosis and chronic kidney disease (CKD) both increase with increasing age, yet there is a paucity of data on treatments for osteoporosis in the setting of impaired kidney function. We examined the efficacy and safety of denosumab (DMAb) among subjects participating in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) Study. We estimated creatinine clearance (eGFR) using Cockcroft-Gault and classified levels of kidney function using the modified National Kidney Foundation classification of CKD. We examined incident fracture rates; changes in bone mineral density (BMD), serum calcium, and creatinine; and the incidence of adverse events after 36 months of follow-up in subjects receiving DMAb or placebo, stratified by level of kidney function. We used a subgroup interaction term to determine if there were differences in treatment effect by eGFR. Most (93%) women were white, and the mean age was 72.3 ± 5.2 years; 73 women had an eGFR of 15 to 29 mL/min; 2817, between 30 to 59 mL/min; 4069, between 60 to 89 mL/min, and 842 had an eGFR of 90 mL/min or greater. None had stage 5 CKD. Fracture risk reduction and changes in BMD at all sites were in favor of DMAb. The test for treatment by subgroup interaction was not statistically significant, indicating that treatment efficacy did not differ by kidney function. Changes in creatinine and calcium and the incidence of adverse events were similar between groups and did not differ by level of kidney function. It is concluded that DMAb is effective at reducing fracture risk and is not associated with an increase in adverse events among patients with impaired kidney function.

Background and objectives: Among hemodialysis patients, achieved hemoglobin is associated with Epoetin alfa dose and erythropoietin responsiveness. A prospective erythropoietin responsiveness measure was developed and its association with mortality evaluated. Design, setting, participants, & measurements: Data from 321 participants were used and randomized to the hematocrit normalization arm of the Normal Hematocrit Cardiac Trial. Subjects were to receive a 50% Epoetin alfa dose increase at randomization. The prospective erythropoietin responsiveness measure was defined as the ratio of weekly hematocrit change (over the 3 wk after randomization) per Epoetin alfa dose increase (1000 IU/wk) corresponding to the mandated 50% dose increase at randomization. The distribution of responsiveness was divided into quartiles. Over a 1-yr follow-up, Cox proportional hazard modeling evaluated associations between this responsiveness measure and mortality. Results: Erythropoietin responsiveness values ranged from −2.1% to 2.4% per week per 1000 IU. Although subjects were similar across response quartiles, mortality ranged between 14% and 34% among subjects in the highest and lowest response quartiles (P = 0.0004), respectively. After adjusting for baseline prognostic indicators, highest versus lowest responsiveness was associated with a hazard ratio of 0.41 (95% confidence interval, 0.20 to 0.87). Conclusion: Lower erythropoietin responsiveness is a strong, independent predictor of mortality risk and should be considered when evaluating associations between clinical outcomes and potential prognostic indicators, such as Epoetin alfa dose and achieved hemoglobin values.

BACKGROUND Routine cancer screening may be of particular importance to women with renal failure, who are at greater risk for cervical, uterine, and colorectal cancer. Most dialysis patients rely on their nephrologists for preventive care. However, this care may not be similar to that provided by primary care physicians. We compared the prevalence of cancer screening between women with and without end-stage renal disease. METHODS Forty-six women on dialysis were compared with 25 women attending an ambulatory care resident clinic and 25 women attending a specialty women's clinic at the same institution. A verbal questionnaire was used to determine if these women received appropriate screening for cervical, breast, and colorectal cancer. RESULTS Women without end-stage renal disease were more likely to receive breast cancer screening (aOR = 5.94, 95% CI: 1.87, 18.9) routine cervical cancer screening (aOR = 4.57, 95% CI: 1.60, 13.1), and colorectal cancer screening (aOR = 2.73, 95% CI: 0.89, 8.39) when compared with women with renal failure . A higher percentage of women on dialysis reported never receiving a recommendation from a physician to obtain cervical or breast cancer screening. CONCLUSIONS African American women on dialysis received less preventive care than did women without end-stage renal disease. Examination of factors influencing preventive screening among dialysis patients is warranted.

Chronic kidney disease (CKD) is associated with cardiovascular (CV) disease and mortality. It is not known whether cardiac rhythm disturbances are more prevalent among individuals with CKD or whether resting electrocardiogram findings predict future CV events in the CKD setting. Data were obtained from the Cardiovascular Health Study, a community-based study of adults aged/=65 yr. After exclusions for prevalent heart disease, atrial fibrillation, implantable pacemaker, or antiarrhythmic medication use, 3238 participants were analyzed. CKD was defined by an estimated GFR60 ml/min per 1.73 m(2). Outcomes were adjudicated incident heart failure (HF), incident coronary heart disease (CHD), and mortality. Participants with CKD had longer PR and corrected QT intervals compared with those without CKD; however, differences in electrocardiographic markers were explained by traditional CV risk factors and CV medication use. After adjustment for known risk factors, each 10-ms increase in the QRS interval was associated with a 15% greater risk for incident HF (95% confidence interval [CI] 1.04 to 1.27), a 13% greater risk for CHD (95% CI 1.04 to 1.24), and a 17% greater risk for mortality (95% CI 1.09, 1.25) among CKD participants. Each 5% increase in QTI was associated with a 42% (95% CI 1.23 to 1.65), 22% (95% CI 1.07 to 1.40), and 10% (95% CI 0.98 to 1.22) greater risk for HF, CHD, and mortality, respectively. Associations seemed stronger for participants with CKD; however, no significant interactions were detected. Resting electrocardiographic abnormalities are common in CKD and independently predict future clinical CV events in this setting.

Kidney dysfunction is associated with bone loss, and patients with ESRD have an increased risk for hip fracture. However, the association of mild to moderate kidney disease with hip fracture has not been studied previously. The association of kidney function with incident hip fracture was examined among participants in the Cardiovascular Health Study, a community-based cohort of older individuals. The primary measure of kidney function was serum cystatin C, a measure that does not depend on lean mass. Hip fractures were identified using International Classification of Diseases, Ninth Revision codes for hospitalizations. A total of 4699 individuals had cystatin C measured in 1992 to 1993 and did not have a hip fracture before cystatin C measurement. The association of kidney function with hip fracture was analyzed with Cox proportional hazards models. Analyses were conducted separately for men and women. After a mean follow-up of 7.1 yr, 195 incident hip fractures occurred in women and 79 occurred in men. Higher cystatin C levels were associated with a higher risk for fracture in women (hazard ratio [HR] 1.26; 95% confidence interval [CI] 1.14 to 1.38 per SD) and in men (HR 1.27; 95% CI 1.11 to 1.46). After multivariable adjustment, higher cystatin C levels were significantly associated with hip fracture in women (HR 1.16; 95% CI 1.01, 1.33) but not in men (HR 1.14; 95% CI 0.86 to 1.52), although the magnitude of the association was similar. Kidney dysfunction, as assessed by cystatin C, is associated with an increased risk for hip fracture. Further studies are needed to evaluate potential mediators of this relationship and to assess whether interventions can decrease this risk.

Darbepoetin alfa, an erythropoiesis-stimulating glycoprotein, has proved efficacious in the treatment of anemia of chronic kidney disease (CKD) in adult subjects. However, little information is available from pediatric populations. We conducted an open-label, non-inferiority, 28-week study comparing the efficacy of darbepoetin alfa with that of recombinant human erythropoietin (rHuEpo) in pediatric subjects with CKD. Subjects, aged 1-18, who were receiving stable rHuEpo treatment (n=124) were randomized (1:2) to either continue receiving rHuEpo or convert to darbepoetin alfa, with doses titrated to achieve and maintain hemoglobin (Hb) levels between 10.0 and 12.5 g/dl. Darbepoetin alfa was considered to be non-inferior to rHuEpo if the lower limit of the two-sided 95% confidence interval (CI) for the difference in the mean change in Hb between the two treatment groups was above -1.0 g/dl. The adjusted mean change in Hb between the baseline and the evaluation period for the rHuEpo and darbepoetin alfa groups was -0.16 g/dl and 0.15 g/dl, respectively, with a difference of 0.31 g/dl (95% CI: -0.45, 1.07) between the means. These results, and the comparable safety profiles, demonstrate that darbepoetin alfa is non-inferior to rHuEpo in the treatment of anemia in pediatric patients with CKD.

Subclinical brain infarcts (SBI) are common in the elderly and are associated with covert neurologic and cognitive impairment. Although renal impairment is associated with accelerated cerebrovascular disease and an increased risk for clinically apparent brain infarct, few studies have examined the relationship between renal function and SBI, and these may have been limited by the inaccuracy of creatinine as a renal function marker. A cross-sectional study was performed among older adults in the Cardiovascular Health Study to examine associations between SBI and two serum markers of renal function: Serum creatinine (SCr) and cystatin C (CysC). Patients had cranial magnetic resonance imaging and renal markers measured in 1992 to 1993. Logistic regression was used to estimate the associations between renal function (estimated by 1/SCr and 1/CysC) and SBI, controlling for potential confounding factors. SBI were present in 789 (28.7%) of 2784 participants. A linear association with SBI was observed for 1/CysC (per 1-SD decrement; odds ratio [OR] 1.20; 95% confidence interval [CI] 1.09 to 1.32; P < 0.001) but not for 1/SCr (OR 1.08; 95% CI 0.98 to 1.19; P = 0.14), for which a quadratic U-shaped association was suggested (P = 0.004). In a model with both markers, 1/CysC was linearly associated with SBI (OR 1.26; P < 0.001), whereas 1/SCr was not (OR 1.06; P = 0.3). The prevalence of SBI was directly associated with quintile of CysC, whereas the association between SCr and SBI was U-shaped, with greater prevalence at high and low levels. Compared with creatinine, CysC, a novel marker of renal function, has a stronger and more direct association with SBI in the elderly.

Observational, patient-oriented research is a term that describes clinical or community-based studies in that they do not involve an experiment or intervention. Observational research studies can be designed and implemented by a primary data collection or using previously collected patient data. The latter is less expensive, although it has some distinct limitations. Many research databases are readily available and can be used to answer important questions that are relevant to kidney disease. This review summarizes the types of research analyses that can be conducted using existing databases, the types of research databases available, and a general approach for addressing a proposed research question using existing data.

Patients with chronic kidney disease (CKD) have a high burden of mortality and cardiovascular morbidity. Additional strategies to modulate cardiovascular risk in this population are needed. Data suggest that anemia is a potent and potentially modifiable risk factor for cardiovascular disease in patients with CKD, but these data remain unsubstantiated by any randomized controlled trial (RCT). Furthermore, the clinical practice guidelines for anemia management in patients with CKD are based on limited data. The need for new RCTs to address critical knowledge deficits, particularly with regard to the impact of anemia therapy on cardiovascular disease and survival, is recognized within the guidelines and independent comprehensive reviews of the existing published trial data.The Trial to Reduce Cardiovascular Events with Aranesp (Amgen Inc, Thousand Oaks, Calif) (darbepoetin alfa) Therapy (TREAT) is a 4000-patient, multicenter, double-blind RCT, designed to determine the impact of anemia therapy with darbepoetin alfa on mortality and nonfatal cardiovascular events in patients with CKD and type 2 diabetes mellitus. Subjects will be randomized in a 1:1 manner to either darbepoetin alfa therapy to a target hemoglobin (Hb) of 13 g/dL or control, consisting of placebo for Hbor =9 g/dL or darbepoetin alfa for Hb9 g/dL until Hb is again Hbor =9 g/dL. TREAT is event-driven and has a composite primary end point comprising time to mortality and nonfatal cardiovascular events, including myocardial infarction, myocardial ischemia, stroke, and heart failure. TREAT will provide data that are critical to evolution of the management of cardiovascular risk in this high-risk population.

Inflammatory and prothrombotic markers are elevated in individuals with mild to moderate renal disease. It was hypothesized that these markers may also be determinants of the progression of renal disease. The association of six markers-serum C-reactive protein (CRP), white blood cell (WBC) count, fibrinogen, factor VII, albumin, and hemoglobin-with subsequent elevations of creatinine and decline in estimated GFR in the Cardiovascular Health Study, a community-based cohort of elderly individuals, was analyzed. Linear regression was used to determine predictors of an annualized change in serum creatinine as the main outcome. Duration of follow-up was 7 yr for the original cohort and 4 yr for the more recently recruited black cohort. A total of 588 (12.7%) individuals had a decline in estimated GFR of at least 3 ml/min per yr per 1.73 m(2). Higher CRP (P < 0.001), WBC count (P < 0.001), fibrinogen (P < 0.001), and factor VII (P < 0.001) levels and lower albumin (P < 0.001) and hemoglobin levels (P < 0.001) were associated with a rise in creatinine, after adjusting for age. With additional adjustments for race, gender, baseline creatinine, systolic and diastolic BP, lipid levels, weight, and pack-years smoking, higher CRP, factor VII, fibrinogen, WBC count, and lower albumin and hemoglobin levels remained associated with a rise in creatinine. Similar results were found for decline in estimated GFR. The decline in GFR was greater with increasing number of inflammatory or prothrombotic markers that were above the median (below for hemoglobin and albumin). Inflammatory and prothrombotic markers are predictors for a change in kidney function in elderly individuals. Interventions that reduce inflammation might confer significant cardiovascular and renal benefits.

Survival following parathyroidectomy among United States dialysis patients. Background Secondary hyperparathyroidism (SHPTH) is highly prevalent among persons with end-stage renal disease (ESRD). SHPTH has been linked to uremic bone disease, vascular calcification, and a higher risk of death. Parathyroidectomy (PTX) can dramatically reduce parathyroid hormone (PTH) and phosphate levels; however, the relationship between PTX and survival is not known. Methods We conducted an observational matched cohort study utilizing data from the United States Renal Database System (USRDS) in which 4558 patients undergoing a first PTX while on hemodialysis or peritoneal dialysis were individually matched by age, race, gender, cause of ESRD, dialysis duration, prior transplantation status, and dialysis modality to 4558 control patients who did not undergo PTX. Patients were followed from the date of PTX until they died or were lost to follow-up. Results The 30-day postoperative mortality rate following PTX was 3.1%. Long-term relative risks of death among patients undergoing PTX were estimated to be 10% to 15% lower than those of matched control patients not undergoing surgery. Survival curves between the 2 groups crossed 587 days following PTX. Median survival was 53.4 months (95% CI: 51.2–56.4) in the PTX group, and 46.8 months (95% CI: 44.7–48.9) in the control group. Conclusion PTX was associated with higher short-term, and lower long-term, mortality rates among U.S. patients receiving chronic dialysis. Measures to attenuate SHPTH may play an important role in reducing mortality among patients with end-stage renal disease.

Background: Frailty has been defined as a tool to define individuals who lack functional reserve and are at risk for functional decline. We hypothesized that chronic renal insufficiency (CRI) would be associated with a greater prevalence of frailty and disability in the elderly. Methods: This cross-sectional analysis used baseline data collected from the Cardiovascular Health Study, which enrolled 5,888 community-dwelling adults aged 65 years or older from 4 clinical centers in the United States. Renal insufficiency is defined as a serum creatinine level of 1.3 mg/dL or greater (≥115 μmol/L) in women and 1.5 mg/dL or greater (≥133 μmol/L) in men. Frailty is defined by the presence of 3 of the following abnormalities: unintentional weight loss, self-reported exhaustion, measured weakness, slow walking speed, and low physical activity. Disability is defined as any self-reported difficulty with activities of daily living. Results: Among 5,808 participants with creatinine levels measured at entry, 15.9% of men (n = 394) and 7.6% of women (n = 254) had CRI. Prevalences of frailty (15% versus 6%; P P = 0.001) were greater in participants with CRI compared with those with normal renal function. After multivariate adjustment for comorbidity, CRI remained significantly associated with frailty (odds ratio, 1.76; 95% confidence interval, 1.28 to 2.41), but not disability (odds ratio, 1.26; 95% confidence interval, 0.94 to 1.69). Conclusion: Elderly persons with CRI have a high prevalence of frailty, which may signal their risk for progression to adverse health outcomes. If confirmed in other studies, identification of frailty in patients with CRI may warrant special interventions to preserve their independence, quality of life, and survival.

i m w m t s T c p S a a g UR UNDERSTANDING of the pathogenesis of bone disorders has progressed coniderably over the past 20 years. In individuals ith normal kidney function, the focus has preominantly been on osteoporosis, whereas in ndividuals with impaired kidney function, the ocus has been on the condition referred to as enal osteodystrophy. This pathologic understandng has led to significant advances in the therapy f bone disease as it affects these patient populaions. Although these advances have tended to ccur in parallel, there has been relatively little ntegration between the two. The work group on Osteoporosis in Chronic idney Disease attempted to deal with the interace between osteoporosis and renal osteodystrohy. We recognized a major problematic issue of efining osteoporosis in relationship to the bone isease observed in the chronic kidney disease CKD) patient. The National Institutes of Health NIH) consensus statement on osteoporosis conains minimal reference to CKD as a cause of econdary osteoporosis. This lack of integration s important for several reasons. First, both fields ikely can learn from advances made in the other; nd second, assessment and management strateies may exhibit exploitable areas of overlap. In he clinical arena in particular, the increasing vailability of dual x-ray absorptiometry (DEXA) nd quantitative computed tomography (qCT) acilities for the measurement of bone mineral ensity (BMD) in both the CKD and non-CKD opulations leads to the frequent identification of

Bone disease is heterogenous and highly prevalent among those with chronic kidney disease, stage V (CKD-V) patients. Although we know much regarding the risk factors and outcomes associated with renal osteodystrophy, less is known about osteoporosis in CKD-V. Factors that predict bone loss in the CKD-V population are similar to those in the general population and include female gender, Caucasian race, older age, chronic disease, and immobility. In addition, some studies suggest that chronic acidosis and renal osteodystrophy may also increase the risk for bone loss. Little is known about associated adverse outcomes or the impact of therapeutic interventions for osteoporosis. Although we know that the risk for hip fracture is high among CKD-V patients and that fracture is associated with an increased risk for death, the role that bone loss plays is largely unknown. Current recommendations suggest that risk-factor modification is the most appropriate course of treatment for CKD-V-associated osteoporosis.

Hepatitis C is both a cause and a complication of chronic renal disease. Chronic infection with hepatitis C virus (HCV) can lead to the immune complex syndromes of cryoglobulinemia and membranoproliferative glomerulonephritis (MPGN). The pathogenetic mechanisms for these conditions have not been defined, although they are clearly caused by the chronic viral infection. Management of HCV-related cryoglobulinemia and MPGN is difficult; antiviral therapy is effective in clearing HCV infection in a proportion of patients, but these conditions can be severe and resistant to antiviral therapy. Hepatitis C also is a complicating factor among patients with end-stage renal disease and renal transplants. The source of HCV infection in these patients can be nosocomial. Screening and careful attention to infection control precautions are mandatory for dialysis units to prevent the spread of hepatitis C. Prevention of spread is particularly important in these patients because HCV infection is associated with significant worsening of survival on dialysis therapy, as well as after kidney transplantation. Furthermore, therapy for hepatitis C is problematic, only partially effective, and associated with significant side effects in this population. There are significant needs in both basic and clinical research in the pathogenesis, natural history, prevention, and therapy for hepatitis C in patients with renal disease.

Pharmacokinetics of oral micronized β-estradiol in postmenopausal women receiving maintenance hemodialysis. Background Although 11% of postmenopausal women with end-stage renal disease (ESRD) are prescribed hormone replacement therapy (HRT), the appropriate use remains poorly explored. Although there remains controversy surrounding the benefits of HRT, it may be of particular interest in this population, which has a high risk of bone loss and a fourfold increase in fracture risk compared to the general population. However, the appropriate dose of estrogen for use in postmenopausal women with ESRD is not known. The objective of this study was to evaluate the steady-state pharmacokinetics of oral micronized β-estradiol in postmenopausal women with ESRD compared with postmenopausal women with normal renal function in order to determine equivalent dosing. Methods Six postmenopausal women with ESRD receiving maintenance hemodialysis and 6 healthy postmenopausal controls received 14days of micronized β-estradiol (1.0mg for control, 0.5mg for ESRD). Blood, urine, and dialysate samples were obtained during a dosage interval on day 14. Estradiol, estrone, albumin, and sex-hormone binding globulin (SHBG) concentrations were determined. Free estradiol concentrations were calculated using a previously described method. Results Women with ESRD had significantly lower serum albumin (610 ± 31 μmol/L vs. 684 ± 83μmol/L) and SHBG (78 ± 17 vs. 118 ± 13nmol/L) than control subjects. Total clearance of estradiol was not significantly different. Due to difference in binding, free estradiol concentrations were significant higher in ESRD women (53.2 ± 17.7pg/mL) than control women (43.5 ± 8.7pg/mL), despite receiving 50% of the dose. There was no significant difference in estrone concentrations. Clearance of both estradiol and estrone in the dialysate was minimal. Conclusion Women with ESRD should receive approximately 50% of the dose typically prescribed to women without ESRD.

Patients with end-stage renal disease (ESRD) treated with dialysis have a dramatically elevated rate of cardiovascular disease (CVD) compared to the general population. Lipid-lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors ("statins") has been shown to markedly reduce cardiovascular risk in patients without renal failure, but their effect has not been fully studied in the dialysis population. In this article we will first discuss the known benefits of statin therapy in the general population and summarize the current guidelines for such therapy. We will then examine the evidence linking dyslipidemia and cardiac disease in the dialysis population and discuss possible pathophysiologic mechanisms by which statins could prevent cardiac disease in these patients. We will also review prior clinical studies of the effects of statins in patients on dialysis, with particular attention to the safety and efficacy of these drugs in this population. Finally, we will review how statins are currently being used in the care of dialysis patients and suggest whether an expanded utilization of these drugs could help reduce the enormously high rates of cardiac disease in this patient population.

Risk factors and mortality associated with calciphylaxis in end-stage renal disease. Background We conducted a case control study to determine risk factors and mortality associated with calciphylaxis in end-stage renal disease. Methods Cases of calciphylaxis diagnosed between December 1989 and January 2000 were identified. Three controls were identified for each hemodialysis patient, with calciphylaxis matched to the date of initiation of hemodialysis. Laboratory data and medication doses were recorded during the 12 months prior to the date of diagnosis and at the time of diagnosis of calciphylaxis. Conditional logistic regression was used to identify risk factors for calciphylaxis. Cox proportional hazards models were used to estimate the risk of death associated with calciphylaxis. Results Nineteen cases and 54 controls were identified. Eighteen patients were hemodialysis patients, and one had a functioning renal allograft. Diagnosis was confirmed by skin biopsy in 16 cases. Women were at a sixfold higher risk of developing calciphylaxis (OR = 6.04, 95% CI 1.62 to 22.6, P = 0.007). There was a 21% lower risk of calciphylaxis associated with each 0.1 g/dL increase in the mean serum albumin during the year prior to diagnosis and at the time of diagnosis of calciphylaxis (OR = 0.79, 95% CI, 0.64 to 0.99, P = 0.037, and OR=0.80, 95% CI, 0.67 to 0.96, P = 0.019, respectively). There was a 3.51-fold increase in the risk of calciphylaxis associated with each mg/dL increase in the mean serum phosphate during the year prior to diagnosis (95% CI, 0.99 to 12.5, P = 0.052). At the time of diagnosis of calciphylaxis, for each 10 IU/L increment in alkaline phosphatase, the risk of calciphylaxis increased by 19% (OR = 1.19, 95% CI, 1.00 to 1.40, P = 0.045). Body mass index, diabetes, blood pressure, aluminum, and higher dosage of erythropoietin and iron dextran were not independent predictors of calciphylaxis. Calciphylaxis independently increased the risk of death by eightfold (OR = 8.58, 95% CI, 3.26 to 22.6, P Conclusions Female gender, hyperphosphatemia, high alkaline phosphatase, and low serum albumin are risk factors for calciphylaxis. Calciphylaxis is associated with a very high mortality.

Many studies of chronic renal disease have reported that men have a more rapid progression of renal insufficiency. However, other studies have found no differences between the sexes, and the true effect of sex on chronic renal disease remains a topic of controversy. There is evidence that women with non-diabetic renal diseases experience a slower progression, but in diabetic renal disease, the effect of gender is not yet established. Sex hormones may mediate the effects of gender on chronic renal disease, through alterations in the renin--angiotensin system, reduction in mesangial collagen synthesis, the modification of collagen degradation, and upregulation of nitric oxide synthesis.

Risk factors for hip fracture among patients with end-stage renal disease. Background Although bone disease is well described among end-stage renal disease (ESRD) patients, little attention has been paid to the occurrence of fracture. We sought to identify factors that are associated with hip fracture among ESRD patients. Methods Data from patients who participated in the United States Renal Data System Dialysis Morbidity and Mortality Study Wave 1 were used for this study. Hip fractures occurring among these patients between 1993 and 1996 were identified from Medicare claims data available from the United States Renal Data System. Cox proportional hazards models were used to estimate the risk of hip fracture associated with demographic and medical variables. Results Of the 4952 patients included in this analysis, 103 sustained a hip fracture. In the multivariate analysis, age (per increasing decade, RR=1.40, 95% CI 1.20, 1.64), female gender (RR = 2.26, 95% CI 1.48, 3.44), race (blacks compared with whites, RR=0.58, 95% CI 0.37, 0.91), body mass index (per 1 unit increase, RR 0.89, 95% CI 0.86, 0.93), and the presence of peripheral vascular disease (RR 1.94, 95% CI 1.29, 2.92) were independently associated with hip fracture. Serum intact parathyroid hormone (iPTH), aluminum, diabetes, and bicarbonate levels did not appreciably influence the risk of hip fracture. Conclusions Demographic and other characteristics that predict risk of hip fracture in the population at large also do so in ESRD patients. However, we could identify no characteristics of ESRD or its treatment that were independently related to hip fracture incidence.

Determinants of type and timing of initial permanent hemodialysis vascular access.BackgroundWe undertook a population-based study of hemodialysis (HD) patients to determine which factors are important in predicting the type of permanent access initially placed and if a functional permanent access is in place at the start of HD.MethodsSelected characteristics were abstracted from the United States Renal Data System (USRDS) Dialysis Morbidity and Mortality Study (DMMS) Wave 2. Logistic regression was used to estimate the independent contribution of specific characteristics in predicting whether the initial permanent access placed was an arteriovenous (AV) fistula compared with a polytetrafluoroethylene (PTFE) graft, and in predicting whether permanent access (fistula or graft) was in place at the initiation of dialysis.ResultsSixty-seven percent of the patients had an AV graft placed as their first permanent access. Characteristics important in predicting if a fistula was initially placed included age (per decade; aOR = 0.84, P < 0.001), female gender (aOR = 0.52, P < 0.001), body mass index (per standard deviation; aOR = 0.70, P = 0.09), avoiding blood draws (aOR = 1.96, P < 0.001), ability to ambulate (aOR = 2.24, P = 0.008), underlying renal disease (glomerular compared with diabetes, aOR = 2.19, P = 0.009), college education (aOR = 1.72, P = 0.002), and sharing in decision making (aOR = 1.50, P = 0.02). Thirty-four percent of patients (34.4%) had functional permanent access at the start of HD. Characteristics important in predicting which patients had functional permanent access included serum albumin (per 1 mg/dL increase, aOR =1.55, P = 0.003), erythropoietin prior to starting HD (aOR = 1.79, P = 0.002), fewer predialysis nephrologist visits (aOR = 0.21, P < 0.001), and when the patient was told they had renal disease (aOR = 0.33, P = 0.002).ConclusionsPTFE grafts were the most common initial permanent access. The majority of patients did not have permanent access at the start of dialysis. Factors that are thought to compromise identification of adequate veins were important predictors of PTFE graft placement. Permanent access at the start of HD was largely a function of early patient education and early referral to a nephrologist.

We evaluated the association between anthropometric measurements and death among pediatric patients with end-stage renal disease (ESRD) using data from the Pediatric Growth and Development Special Study (PGDSS) from the US Renal Data System. Height, growth velocity, and body mass index (BMI) were used for the analysis of 1,949 patients in the PGDSS. To standardize these measurements, SD scores (SDSs) were calculated using population data from the Third National Health and Nutrition Examination Survey. Using Cox proportional hazards models, we assessed the association between anthropometric measures and death, controlling for demographic factors and stratifying by age. Multivariate analysis showed that each decrease by 1 SDS in height was associated with a 14% increase in risk for death (adjusted relative risk [aRR], 1.14; 95% confidence interval [CI], 1.02 to 1.27; P = 0.017). For each 1 SDS decrease in growth velocity among patients in our sample, the risk for death increased by 12% (aRR, 1.12; 95% CI, 1.00 to 1.25; P = 0.043). There was a statistically significant U-shaped association between BMI and death (P = 0.001), with relatively low and high BMIs associated with an increased risk for death. In children with ESRD, growth delay and extremes in BMI are associated with an increased risk for mortality.

Increased risk of hip fracture among patients with end-stage mated 300,000 hip fractures in the United States (1), with renal disease. an associated cost of close to $10 billion per year (2). Background. Although patients with end-stage renal disease In addition to the economic impact, hip fractures are (ESRD) are at increased risk for bone loss, the risk of hip frac- associated with an increase risk of morbidity and mortal- ture in this population is not known. We compared the risk of ity (3-5). Several investigators have shown that patients hip fracture among dialysis patients with the general population. Methods. We used data from the United States Renal Data with end-stage renal disease (ESRD) have reduced bone System (USRDS) to identify all new Caucasian dialysis patients mineral density, a risk factor for fracture in the general who began dialysis between January 1, 1989, and December population (6-8). In addition, a cross-sectional study re- 31, 1996. All hip fractures occurring during this time period ported that osteopenia among Japanese men with renal were ascertained. The observed number of hip fractures was failure was associated with an increased risk for vertebral compared with the expected number based on the experience of residents of Olmstead County (MN, USA). Standardized fracture (9). However, the incidence and relative risk of incidence ratios were calculated as the ratio between observed hip fracture in dialysis patients compared with the gen- and expected. The risk attributable to ESRD was calculated eral population are not known. We conducted a popula- as the difference between the observed and expected rate of tion-based cohort study to estimate the risk of hip frac- hip fracture per 1000 person-years. ture among Caucasian dialysis patients compared with Results. The number of dialysis patients was 326,464 (55.9% male and 44.1% female). There were 6542 hip fractures ob- the general U.S. population. served during the follow-up period of 643,831 patient years. The overall incidence of hip fracture was 7.45 per 1000 person years for males and 13.63 per 1000 person years for females. METHODS The overall relative risk for hip fracture was 4.44 (95% CI, Patients 4.16 to 4.75) for male dialysis patients and 4.40 (95% CI, 4.17 This study used data from the United States Renal to 4.64) for female dialysis patients compared with people of the same sex in the general population. While the age-specific Data System (USRDS). The details of the USRDS relative risk of hip fracture was highest in the youngest age data collection techniques are described elsewhere (10). groups, the added risks of fracture associated with dialysis rose Briefly, the USRDS collects information on the inci- steadily with increasing age. The relative risk of hip fracture dence, prevalence, treatment, morbidity, and mortality increased as time since first dialysis increased. of ESRD patients who have survived more than 90 days

Prescription of hormone replacement therapy in postmenopausal women with renal failure.BackgroundAlthough patients with end-stage renal disease (ESRD) are at increased risk for early menopause, osteoporosis, cognitive dysfunction, and cardiovascular disease, few postmenopausal women are prescribed hormone replacement therapy (HRT). The reasons for the low prescription rate are not known. This study uses data from the United States Renal Data System (USRDS) to assess the prevalence and predictors of HRT use in postmenopausal women with ESRD.MethodsData were obtained from the USRDS Dialysis Morbidity and Mortality Study Wave 2. All women who were at least 45 years of age were considered postmenopausal and were selected for our analysis. Demographics, behavior and medical characteristics were abstracted from the database. Logistic regression was used to estimate the independent contribution of population characteristics in predicting the use of HRT. Linear regression models were used to estimate the relationship between HRT use and both triglycerides and total cholesterol.ResultsThe overall prevalence of HRT prescription was 10.8%. Important predictors of HRT use included age (aOR = 0.74, 95% CI 0.13 to 0.88, P < 0.001), black ethnicity (aOR = 0.50, 95% CI, 0.31 to 0.78, P < 0.002), college education (aOR = 3.00, 95% CI, 1.70 to 5.24, P < 0.001), and the ability to ambulate (aOR = 1.99, 95% CI, 1.01 to 3.91, P = 0.05). Serum triglyceride and total cholesterol levels were higher among women treated with HRT than among those not treated with HRT (264 ± 155 vs. 217 ± 159 mg/dl, P = 0.001 and 220 ± 62 vs. 209 ± 55 mg/dl, P = 0.02, respectively).ConclusionsHRT is prescribed less frequently in postmenopausal ESRD patients than in the general population. Younger age, higher education levels, white race, and the ability to ambulate were important predictors of HRT use. Targeting populations of patients who are likely to benefit from but less likely to be prescribed HRT may increase the prescription of HRT.

The cyclin kinase inhibitor p21 WAF1/CIP1 is required for glomerular hypertrophy in experimental diabetic nephropathy. Background Diabetic nephropathy is characterized by glomerular hypertrophy. We have recently shown that experimental diabetes mellitus is associated with an increase in glomerular expression of the cyclin kinase inhibitor p21 WAF1/CIP1 (p21). Furthermore, in vitro glucose-induced mesangial cell hypertrophy is also associated with an up-regulated expression of p21. In this study, we tested the hypothesis that p21 mediates diabetic glomerular hypertrophy in vivo . Methods Experimental diabetes mellitus was induced by streptozotocin in mice in which p21 was genetically deleted (p21 -/-) and in wild-type mice (p21 +/+). Kidney biopsies were obtained from diabetic and control (citrate injected) p21 +/+ and p21 -/- mice at day 60. The tissue was used for morphologic studies of glomerular size (measured by computer image-analysis system), glomerular cellularity (cell count), glomerular matrix expansion (silver stain), apoptosis (TUNEL), and expression of transforming growth factor-βbgr; 1 (TGF-βbgr; 1 ) by in situ hybridization. Results The glomerular tuft area increased 11.21% in diabetic p21 +/+ mice at day 60 compared with control (3329.98 ± 244.05 μm 2 vs. 2994.39 ± 176.22 μm 2 , P = 0.03), and the glomerular cell count did not change in diabetic p21 +/+ mice at day 60 compared with the control. These findings are consistent with glomerular hypertrophy. In contrast, the glomerular tuft area did not increase in diabetic p21 -/- mice at day 60 compared with the control (3544.15 ± 826.49 vs. 3449.15 ± 109.65, P = 0.82), nor was there an increase in glomerular cell count (41.41 ± 13.18 vs. 46.95 ± 3.00, P = 0.43). Diabetic p21 +/+ mice, but not p21 -/- mice, developed an increase in proteinuria at day 60 compared with the control. Tubular cell proliferation, measured by proliferating cell nuclear antigen immunostaining, was increased in both diabetic p21 +/+ (2.1-fold) and p21 -/- (7.61-fold) mice compared with controls. Glomerular cell apoptosis did not increase in diabetic mice. Although glomerular TGF-βbgr; 1 mRNA levels increased in both strains of diabetic mice at day 60, the glomerular matrix did not expand. Conclusions Hyperglycemia was associated with glomerular hypertrophy in p21 +/+ mice. Despite the increase in TGF-βbgr; 1 mRNA, diabetic p21 -/- mice did not develop glomerular hypertrophy, providing evidence that the cyclin kinase inhibitor p21 may be required for diabetic glomerular hypertrophy induced by TGF-βbgr; 1 . The loss of p21 increases tubular but not glomerular cell proliferation in diabetic nephropathy. The absence of glomerular hypertrophy appears protective of renal function in diabetic mice.

This study describes the occurence of hepatitis C virus (HCV) infection in the setting of focal segmental glomerular sclerosis (FSGS). All patients with the pathologic diagnosis of idiopathic FSGS between 1992 and 1996 at the University of Washington Hospitals were examined using a retrospective cohort study design. FSGS was determined by renal biopsy in the absence of secondary causes. Demographic, laboratory, and outcome data were collected in a standardized fashion. Six patients (50%) were infected with HCV. Patients with HCV infection and FSGS were primarily Black (67%), hypertensive (100%), had a history of intravenous drug abuse (83%), and had normal liver enzymes. Those with HCV infection and a history of IVDA appeared clinically and histologically similar to previously described cases of ‘heroin nephropathy’. We demonstrate that there is a high prevalence of HCV infection in our population of patients with idiopathic FSGS. Although this may simply reflect an epiphenomenon, we propose that HCV infection may play a role in the development of FSGS in a predisposed host.

Posttransplant lymphoproliferative disorder (PTLD) has been treated with decreased immunosuppression, antiviral medications, anti-B lymphocyte agents, radiation therapy, and/or chemotherapy. However, a standardized stepwise approach to treatment has not been previously evaluated. In the present study, 19 consecutive patients presenting to a single institution with newly diagnosed PTLD were treated according to a sequential protocol that consisted of (1) a reduction in immunosuppressive medications plus, if feasible, resection or definitive radiation therapy of localized disease, (2) interferon-α, and (3) systemic chemotherapy. Of the 3 patients presenting exclusively with localized disease, two were treated with resection of pulmonary parenchymal nodules and one was treated with radiation therapy to a paraspinous mass, without evidence of recurrence at a mean follow-up of 31 months (range, 8 to 46 months). Sixteen patients presented with PTLD not amenable to local therapy, and they were treated daily with 3×10 6 units/m 2 subcutaneous interferon-a. Total regression of PTLD (defined as disappearance of the tumor mass by physical examination or computed tomography scanning) was found in 8 of 14 patients who received at least 3 weeks of interferon therapy. Interferon-α therapy was continued for 6 to 9 months in the eight patients judged to be responders. None of these patients have relapsed to date with the same neoplastic clone. Two patients, however, developed new neoplastic clones. Seven patients received systemic chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) (n=1), EPOCH (etoposide, vincristine, and doxorubicin administered as a continuous infusion, with an intravenous bolus of cyclophosphamide and oral prednisone) (n=4), or EPOCH followed by DHAP (dexamethasone, cytarabine, and cisplatin) (n=2) after failure of interferon-a; five patients had a complete response. Only 1 of the 19 patients died of uncontrolled PTLD. These results suggest that the majority of solid organ transplant recipients who develop PTLD can be safely and successfully treated using a sequential approach to therapy.

Hepatitis C virus (HCV) infection is highly prevalent among chronic dialysis patients (10% to 40%) and is the most common cause of chronic liver disease. However, there are no studies estimating the risk for death among dialysis patients infected with HCV compared with those not infected. We conducted a prospective cohort study to estimate the risk for death among chronic dialysis patients infected with HCV compared with those not infected. In 1992, 200 patients (91%) who had been undergoing dialysis therapy for at least 6 months consented to be screened for HCV infection by enzyme immunoblot assay and polymerase chain reaction (PCR). Information about potential confounders and potential risk factors for death and HCV infection was obtained from the dialysis center database. Patient outcomes collected included death, transplantation, and loss to follow-up. The Cox proportional hazards model was used to estimate the odds of death among dialysis patients who were positive for the HCV antibody and HCV RNA compared with negative patients. Forty-four patients (22%) were HCV antibody positive. Thirty-four patients (17%) were HCV RNA positive. Patients in the HCV RNA-positive group were more likely to be younger (51.8+/-12.6 v 57.2+/-17.3 years of age), men (77% v 54%), and black (65% v 37%). None of the home hemodialysis or peritoneal dialysis patients were HCV RNA positive, whereas one of the home hemodialysis and one of the peritoneal dialysis patients were HCV antibody positive. Two patients became infected with HCV during the follow-up period. Patients who were HCV RNA positive and those who were HCV antibody positive were at increased risk for death compared with patients who were negative (adjusted relative risk [aRR]=1.78; 95% confidence interval [CI], 1.01 to 3.14; P=0.045; and aRR=1.97; 95% CI, 1.16 to 3.33; P=0.012, respectively), after adjusting for time on dialysis, race, transplantation, and age. We conclude that HCV infection increased the risk for death during the study period compared with those not infected. Further studies should assess the measures used to prevent and treat HCV infection. (Am J Kidney Dis 1998 Oct;32(4):629-34)

Chronic kidney disease affects over ten million Americans. Most severely affected patients undergo dialysis or transplantation at high economic and human cost. Each year, 70,000 Americans die from causes related to kidney failure. Health-related quality of life has been an important area of investigation. Recent advances include the development of new instruments that better distinguish among treatment modalities and differing patient populations. This article provides a brief state-of-the-art review of health-related quality of life instruments in chronic kidney disease, describes issues affecting patients, factors associated with decreased health-related quality of life and summarizes studies of health-related quality of life in this population. It concludes with our recommendations for further work and a look at what the future might hold.

To evaluate the efficacy and safety of darbepoetin alfa dosed every-other-week (Q2W) to treat anemia in subjects with chronic kidney disease (CKD), not receiving dialysis, who were naïve to erythropoiesis-stimulating agent (ESA) therapy.This was an open-label, multicenter, single-arm study enrolling ESA-naïve CKD subjects with baseline hemoglobin (Hb)11.0 g/dL. Q2W darbepoetin alfa treatment was initiated at a dose of 0.75 microg/kg and titrated to achieve and maintain Hb levels at 11.0-13.0 g/dL. Treatment was administered from week 1 to week 19.The primary endpoint was the proportion of subjects who achieved Hbor = 11 g/dL at any study visit, except in week 1. Hb levels, darbepoetin alfa dose, and safety were also assessed.Of the 128 subjects who received at least one dose of darbepoetin alfa and of the subjects who completed the study, 118 (92%) and 112 (97%), respectively, achieved a Hbor = 11 g/dL in a median time of 5 weeks. Median darbepoetin alfa dose at week 1 and at the time of achieving a Hbor = 11 g/dL were 60 and 80 microg, respectively. Darbepoetin alfa was well-tolerated, and short-term adverse events were consistent with those expected in CKD subjects.This study demonstrates that de novo Q2W darbepoetin alfa was effective in correcting and maintaining Hb levels in ESA-naïve subjects with CKD who were not receiving dialysis. Study limitations, including lack of a control arm for the study and multiple race information for subjects, must be considered in interpreting the results.ClinicalTrials.gov, NCT00112008.

The mortality rate in children with ESRD is substantially lower than the rate experienced by adults. However, the risk of death while awaiting kidney transplantation and the impact of transplantation on long-term survival has not been well characterized in the pediatric population. We performed a longitudinal study of 5961 patients under age 19 who were placed on the kidney transplant waiting list in the United States. Of these, 5270 received their first kidney transplant between 1990 and 2003. Survival was assessed via a time-varying nonproportional hazards model adjusted for potential confounders. Transplanted children had a lower mortality rate (13.1 deaths/1000 patient-years) compared to patients on the waiting list (17.6 deaths/1000 patient-years). Within the first 6 months of transplant, there was no significant excess in mortality compared to patients remaining on the waiting list (adjusted Relative Risk (aRR) = 1.01; p = 0.93). After 6 months, the risk of death was significantly lower: at 6-12 months (aRR = 0.37; p < 0.001) and at 30 months (aRR 0.26; p < 0.001). Compared to children who remain on the kidney transplant waiting list, those who receive a transplant have a long-term survival advantage. With the potential for unmeasured bias in this observational data, the results of the analysis should be interpreted conservatively.

Background: The anemia of chronic kidney disease (CKD) is associated with increased hospitalizations, increased cardiovascular morbidity and mortality, and diminished quality of life in the elderly. Darbepoetin alfa is an erythropoiesis-stimulating agent that has been shown to be effective in treating anemia in patients with CKD (but not on dialysis) when administered using extended-dosing regimens. Objective: The purpose of this post hoc analysis was to examine the efficacy and safety profile of once-monthly (QM) darbepoetin alfa in study patients stratified according to age (ie

Coronary artery calcification (CAC) is prevalent and predicts mortality among patients with ESRD, but whether less severe kidney dysfunction is associated with CAC is uncertain. To address this question, 6749 participants of the Multi-Ethnic Study of Atherosclerosis, who were middle-aged and without known cardiovascular disease, were evaluated. Renal function was categorized by cystatin C quartiles and estimated GFR (eGFR; < to >60 ml/min per 1.73 m2), and CAC was evaluated by computed tomography (CT). Fifty percent of participants had CAC, mean cystatin C was 0.90 mg/L, and 10% had eGFR

Objective. To demonstrate the efficacy and safety of once-monthly (QM) darbepoetin alfa administration in maintaining haemoglobin (Hb) 11.0–13.0 g dL−1 in subjects with chronic kidney disease (CKD) not receiving dialysis and previously treated with darbepoetin alfa every other week (Q2W). Subjects. This open-label study enrolled subjects ≥18 years of age who had glomerular filtration rate ≥15 and ≤60 mL min−1/1.73 m2, had Hb 11.0–13.0 g dL−1, and were receiving Q2W darbepoetin alfa. Design. Subjects were switched to QM darbepoetin alfa therapy for 28 weeks; the QM dose was titrated to maintain Hb levels. Primary end-point: proportion of subjects maintaining Hb ≥11.0 g dL−1 during the final 8 weeks of the study (evaluation phase). Secondary end-points: Hb concentration during evaluation, darbepoetin alfa dose during the study, adverse events, laboratory parameters, and blood pressure. Results. The study enrolled 152 subjects (female 52%, white 64%). Mean Hb ≥11.0 g dL−1 during evaluation was achieved by 76% of the 150 subjects who received at least one dose of darbepoetin alfa [95% confidence interval (CI): 68%, 83%]. Mean (SD) Hb during evaluation was 11.71 (0.92) g dL−1. Eighty-five per cent of 129 subjects who completed the study (95% CI: 78%, 91%) had Hb ≥11.0 g dL−1 during evaluation. The dose of darbepoetin alfa over the study period was median (95% CI) 124.4 μg (106.2, 140.0). Darbepoetin alpha administered QM was well tolerated in study subjects. Conclusion. Darbepoetin alpha administered QM maintained Hb in study subjects with CKD not receiving dialysis.

Cystatin C is an alternative measure of kidney function that may have prognostic importance among elderly persons who do not meet standard criteria for chronic kidney disease (estimated glomerular filtration rate [GFR]or =60 mL/min per 1.73 m2).To evaluate cystatin C as a prognostic biomarker for death, cardiovascular disease, and incident chronic kidney disease among elderly persons without chronic kidney disease.Cohort study.The Cardiovascular Health Study, a population-based cohort recruited from 4 communities in the United States.4663 elderly persons.Measures of kidney function were creatinine-based estimated GFR by using the Modification of Diet in Renal Disease equation and cystatin C concentration. Outcomes were death, cardiovascular death, noncardiovascular death, heart failure, stroke, myocardial infarction, and incident chronic kidney disease during follow-up (median, 9.3 years).At baseline, 78% of participants did not have chronic kidney disease (estimated GFRor =60 mL/min per 1.73 m2) and mean cystatin C concentration, creatinine concentration, and estimated GFR were 1.0 mg/L, 79.6 micromol/L (0.9 mg/dL), and 83 mL/min per 1.73 m2, respectively. Cystatin C concentrations (per SD, 0.18 mg/L) had strong associations with death (hazard ratio, 1.33 [95% CI, 1.25 to 1.40]), cardiovascular death (hazard ratio, 1.42 [CI, 1.30 to 1.54]), noncardiovascular death (hazard ratio, 1.26 [CI, 1.17 to 1.36]), incident heart failure (hazard ratio, 1.28 [CI, 1.17 to 1.40]), stroke (hazard ratio, 1.22 [CI, 1.08 to 1.38]), and myocardial infarction (hazard ratio, 1.20 [CI, 1.06 to 1.36]) among these participants. Serum creatinine concentrations had much weaker associations with each outcome and only predicted cardiovascular death. Participants without chronic kidney disease who had elevated cystatin C concentrations (or =1.0 mg/L) had a 4-fold risk for progressing to chronic kidney disease after 4 years of follow-up compared with those with cystatin C concentrations less than 1.0 mg/L.Because this study did not directly measure GFR or albuminuria, the extent to which cystatin C may be influenced by nonrenal factors was not determined and participants with albuminuria might have been misclassified as having no kidney disease.Among elderly persons without chronic kidney disease, cystatin C is a prognostic biomarker of risk for death, cardiovascular disease, and chronic kidney disease. In this setting, cystatin C seems to identify a "preclinical" state of kidney dysfunction that is not detected with serum creatinine or estimated GFR.

Chronic kidney disease is associated with a higher risk for cardiovascular mortality, as well as all-cause mortality. Whether chronic kidney disease is a predictor of noncardiovascular mortality is less clear. To further explore the latter, the association of kidney function with total noncardiovascular mortality and cause-specific mortality was assessed in the Cardiovascular Health Study, a community-based cohort of older individuals. Kidney disease was assessed using cystatin C and estimated GFR in 4637 participants in 1992 to 1993. Participants were followed until June 30, 2001. Deaths were adjudicated as cardiovascular or noncardiovascular disease by committee, and an underlying cause of death was assigned. The associations of kidney function with total noncardiovascular mortality and cause-specific mortality were analyzed by proportional hazards regression. Noncardiovascular mortality rates increased with higher cystatin C quartiles (16.8, 17.1, 21.6, and 50.0 per 1000 person-years). The association of cystatin C with noncardiovascular mortality persisted after adjustment for demographic factors; the presence of diabetes, C-reactive protein, hemoglobin, and prevalent cardiovascular disease; and measures of atherosclerosis (hazard ratio 1.69; 95% confidence interval 1.33 to 2.15, for the fourth quartile versus the first quartile). Results for estimated GFR were similar. The risk for noncardiac deaths attributed to pulmonary disease, infection, cancer, and other causes was similarly associated with cystatin C levels. Kidney function predicts noncardiovascular mortality from multiple causes in the elderly. Further research is needed to understand the mechanisms and evaluate interventions to reduce the high mortality rate in chronic kidney disease.

Cystatin C is a serum measure of renal function that appears to be independent of age, sex, and lean muscle mass. We compared creatinine and cystatin C levels as predictors of mortality from cardiovascular causes and from all causes in the Cardiovascular Health Study, a cohort study of elderly persons living in the community.Creatinine and cystatin C were measured in serum samples collected from 4637 participants at the study visit in 1992 or 1993; follow-up continued until June 30, 2001. For each measure, the study population was divided into quintiles, with the fifth quintile subdivided into thirds (designated 5a, 5b, and 5c).Higher cystatin C levels were directly associated, in a dose-response manner, with a higher risk of death from all causes. As compared with the first quintile, the hazard ratios (and 95 percent confidence intervals) for death were as follows: second quintile, 1.08 (0.86 to 1.35); third quintile, 1.23 (1.00 to 1.53); fourth quintile, 1.34 (1.09 to 1.66); quintile 5a, 1.77 (1.34 to 2.26); 5b, 2.18 (1.72 to 2.78); and 5c, 2.58 (2.03 to 3.27). In contrast, the association of creatinine categories with mortality from all causes appeared to be J-shaped. As compared with the two lowest quintiles combined (cystatin C level,or =0.99 mg per liter), the highest quintile of cystatin C (or =1.29 mg per liter) was associated with a significantly elevated risk of death from cardiovascular causes (hazard ratio, 2.27 [1.73 to 2.97]), myocardial infarction (hazard ratio, 1.48 [1.08 to 2.02]), and stroke (hazard ratio, 1.47 [ 1.09 to 1.96]) after multivariate adjustment. The fifth quintile of creatinine, as compared with the first quintile, was not independently associated with any of these three outcomes.Cystatin C, a serum measure of renal function, is a stronger predictor of the risk of death and cardiovascular events in elderly persons than is creatinine.

Previous studies that evaluated the association of kidney function with incident heart failure may be limited by the insensitivity of serum creatinine concentration for detecting abnormal kidney function.To compare serum concentrations of cystatin C (a novel marker of kidney function) and creatinine as predictors of incident heart failure.Observational study based on measurement of serum cystatin C from frozen sera obtained at the 1992-1993 visit of the Cardiovascular Health Study. Follow-up occurred every 6 months.Adults 65 years of age or older from 4 communities in the United States.4384 persons without previous heart failure who had measurements of serum cystatin C and serum creatinine.Incident heart failure.The mean (+/-SD) serum concentrations of cystatin C and creatinine were 82 +/- 25 nmol/L (1.10 +/- 0.33 mg/L) and 89 +/- 34 micromol/L (1.01 +/- 0.39 mg/dL), respectively. During a median follow-up of 8.3 years (maximum, 9.1 years), 763 (17%) participants developed heart failure. After adjustment for demographic factors, traditional and novel cardiovascular risk factors, cardiovascular disease status, and medication use, sequential quintiles of cystatin C concentration were associated with a stepwise increased risk for heart failure in Cox proportional hazards models (hazard ratios, 1.0 [reference], 1.30 [95% CI, 0.96 to 1.75], 1.44 [CI, 1.07 to 1.94], 1.58 [CI, 1.18 to 2.12], and 2.16 [CI, 1.61 to 2.91]). In contrast, quintiles of serum creatinine concentration were not associated with risk for heart failure in adjusted analysis (hazard ratios, 1.0 [reference], 0.77 [CI, 0.59 to 1.01], 0.85 [CI, 0.64 to 1.13], 0.97 [CI, 0.72 to 1.29], and 1.14 [CI, 0.87 to 1.49]).The mechanism by which cystatin C concentration predicts risk for heart failure remains unclear.The cystatin C concentration is an independent risk factor for heart failure in older adults and appears to provide a better measure of risk assessment than the serum creatinine concentration. *For a full list of participating Cardiovascular Health Study investigators and institutions, see http://www.chs-nhlbi.org.

Cinacalcet HCl attenuates parathyroid hyperplasia in a rat model of secondary hyperparathyroidism . Background Secondary hyperparathyroidism (HPT) in chronic kidney disease (CKD) is a physiologic response to kidney failure characterized by elevated serum parathyroid hormone (PTH) levels and parathyroid gland enlargement. Calcimimetic agents acting through allosteric modification of the calcium-sensing receptor (CaR) can attenuate parathyroid hyperplasia in rats with secondary HPT. The present study explores the effects of the calcimimetic cinacalcet HCl on parathyroid hyperplasia, apoptosis, and PTH secretion in a rat model of secondary HPT. Methods Cinacalcet HCl was gavaged daily (1, 5, or 10 mg/kg) for 4 weeks starting 6 weeks post-5/6 nephrectomy. After dosing, hyperplasia was determined using parathyroid weight and proliferating cell nuclear antigen (PCNA) immunochemistry. Apoptosis was determined using in situ techniques. Serum PTH (1–34) and blood chemistries were determined throughout the course of the study. Results Administration of cinacalcet HCl (5 or 10 mg/kg) significantly reduced the number of PCNA-positive cells and decreased parathyroid weight compared with vehicle-treated 5/6 nephrectomized rats. There was no difference in apoptosis from cinacalcet HCl–treated or vehicle-treated animals. Serum PTH and blood ionized calcium levels decreased in cinacalcet HCl–treated animals compared with vehicle-treated controls. Conclusion The results confirm previous work demonstrating that calcimimetic agents attenuate the progression of parathyroid hyperplasia in subtotally nephrectomized rats, extending earlier observations to now include cinacalcet HCl. These results support a role for the CaR in regulating parathyroid cell proliferation. Therefore, cinacalcet HCl may represent a novel therapy for improving the management of secondary HPT.

Renal impairment is associated with an increased risk of carotid atherosclerosis and stroke, determinants of cognitive dysfunction and dementia. The purpose of this study was to determine whether moderate renal impairment is associated with incident dementia among community-dwelling older adults. Participants in the Cardiovascular Health Cognition Study without prevalent dementia ( n = 3349) were included in the analysis. Incident dementia was confirmed through neurologic testing. Renal function at baseline was estimated by the inverse of serum creatinine (1/SCr); moderate renal impairment was defined as SCr ≥ 1.3 mg/dl for women and ≥ 1.5 mg/dl for men. Cox regression models were used to estimate the association of renal impairment with incident dementia. Because SCr is also a function of muscle mass, the authors determined whether the relationship between SCr and dementia was particularly strong among individuals without severe co-morbidity at baseline, as reflected by self-reported general health status. There were 477 incident dementia cases over a median 6 yr follow-up. After adjustment for potential confounders, moderate renal insufficiency was associated with a 37% increased risk of dementia (95% CI = 1.06 to 1.78). Similarly, a 0.5-unit decrement in 1/SCr (equivalent to an increase in SCr from 1.0 to 2.0 mg/dl) was associated with a 26% increased risk (95% CI = 1.02 to 1.60). These associations were present only among the 84% of older adults who reported good–excellent health. Among those in good–excellent health, higher SCr was associated with vascular-type dementia but not Alzheimer-type dementia. Moderate renal impairment, reflected by a higher SCr, is associated with an excess risk of incident dementia among individuals in good–excellent health. Strategies to prevent or delay the onset of dementia in patients with moderate renal impairment are needed.

In the Cardiovascular Health Study, the authors sought to evaluate the impact of chronic renal insufficiency (CRI) on cardiovascular risk status and outcomes in a representative sample of community-dwelling elderly adults. Defined as a serum creatinine levelor =1.3 mg/dL in women andor =1.5 mg/dL in men, CRI was present in 647 (11%) of 5808 participants. At baseline, the prevalence of clinical or subclinical cardiovascular disease was 64% in participants with CRI and 43% in those without CRI (odds ratio, 2.34; 95% confidence interval, 1.96-2.80). The incidence of cardiovascular disease events during follow-up was 3% per year in participants with creatinine levels1.10 mg/dL and increased steadily to reach 7% per year in those with creatinineor =1.70 mg/dL. Among the possible mediators for the association between CRI and cardiovascular morbidity are inflammatory (C-reactive protein, fibrinogen, and interleukin-6) and hemostatic (factor VII, factor VIII, plasmin-antiplasmin product, and D-dimer) biomarkers, all of which were significantly elevated in Cardiovascular Health Study participants with CRI. Future studies should evaluate the contribution of novel and traditional cardiovascular risk factors to the cardiovascular risk of elderly persons with CRI. The identification of CRI in the elderly and the use of cardiovascular prevention therapies represent a major opportunity to reduce their burden of cardiovascular morbidity.

Small changes in creatinine levels have been incrementally associated with increased risk for heart failure morbidity, but their association with cardiovascular events has not been evaluated in persons with established coronary heart disease (CHD).This was an observational study from the Heart and Estrogen/Progestin Replacement Study (HERS) and the HERS-II follow-up study. Participants were 2,763 postmenopausal women with CHD who were followed up for a mean of 4.1 years during HERS and an additional 2.7 years during HERS-II. We evaluated the association of worsened renal function (creatinine level increaseor = 0.3 mg/dL [or =26.5 micromol/L]) during HERS with CHD outcomes (nonfatal myocardial infarction and CHD death) that occurred during HERS-II.Only 194 participants (9%) had worsened renal function during HERS, and they were characterized by a greater prevalence of diabetes, lower high-density lipoprotein cholesterol and higher triglyceride levels, and increased rate of cardiovascular events during HERS (all P0.01). After adjustment for only baseline creatinine levels, worsened renal function was associated with HERS-II CHD events (relative hazard [RH], 1.54; 95% confidence interval [CI], 1.04 to 2.29). After adjustment for baseline characteristics, HERS cardiovascular events, and medication use, worsened renal function was no longer associated with CHD events (RH, 1.08; 95% CI, 0.70 to 1.67). However, baseline creatinine levels from HERS were remarkably strong predictors of HERS-II events.Although baseline renal function was among the strongest predictors of CHD events during 7 years of HERS follow-up, we found no significant association of worsened renal function with cardiovascular outcomes after adjustment for cardiovascular risk factors and interim events.

Background: Hypertension is a common complication of pregnancy. Previous evidence has linked pregnancy-related hypertension to maternal cardiovascular disease. We conducted a population-based cohort study to estimate the risks for cardiovascular and thromboembolic events in women with pregnancy-related hypertension. Methods: We analyzed data from all singleton births recorded in Washington State from 1987 to 1998. Mothers were classified as having gestational hypertension, preeclampsia, or chronic hypertension based on hospital discharge and birth record information. Birth records were linked to subsequent hospitalizations within Washington State. Proportional hazards models were used to estimate the relationship between each form of pregnancy-related hypertension and subsequent risk for cardiovascular and thromboembolic events. Results: We identified 31,239 eligible hypertensive pregnancies from 807,010 births. During follow-up, there were 118 hospitalizations for a first acute cardiovascular event and 172 hospitalizations for a first thromboembolic event. Gestational hypertension, mild preeclampsia, and severe preeclampsia were associated with 2.8-fold (95% confidence interval [CI], 1.6 to 4.8), 2.2-fold (95% CI, 1.3 to 3.6), and 3.3-fold (95% CI, 1.7 to 6.5) greater risks for cardiovascular events, respectively. Severe preeclampsia was associated with a 2.3-fold (95% CI, 1.3 to 4.2) greater risk for thromboembolic events. Conclusion: Preeclampsia and gestational hypertension are associated with increased risk for cardiovascular events. Pregnancy-induced hypertension appears to be an important risk factor for the development of future cardiovascular disease in young women.

Although patients with ESRD experience markedly higher rates of stroke, no studies in the US have identified risk factors associated with stroke in this population. It was hypothesized that black race, malnutrition, and elevated BP would be associated with the risk of stroke among patients with ESRD. Data from the United States Renal Data Systems were used. Adult Medicare-insured hemodialysis and peritoneal dialysis patients without a history of stroke or transient ischemic attack (TIA) were considered for analysis. The primary outcome was hospitalized or fatal stroke. Cox proportional hazards models were used to determine the associations between the primary predictor variables and stroke. The rate of incident stroke was 33/1,000 person-years in the study sample. After adjustment for age and other patient characteristics, three markers of malnutrition were associated with the risk of stroke-serum albumin (per 1 g/dl decrease, hazard ratio [HR] = 1.43), height-adjusted body weight (per 25% decrease, HR = 1.09), and a subjective assessment of undernourishment (HR = 1.27)-as was higher mean BP (per 10 mmHg, HR = 1.11). The association between black race varied by cardiac disease status, with blacks estimated to be at lower risk than whites among individuals with cardiac disease (HR = 0.74), but at higher risk among individuals without cardiac disease (HR = 1.24). This study confirms the extraordinarily high rates of stroke in ESRD patients on dialysis and identifies high mean BP and malnutrition as potentially modifiable risk factors. The association between black race and stroke differs by cardiac disease status; the reasons for this differing effect of race deserve further investigation.

Elevated risk of stroke among patients with end-stage renal disease. Background Although end-stage renal disease (ESRD) has been associated with accelerated vascular disease of the cerebral circulation, there are no prior studies that have estimated the risk of hemorrhagic and ischemic stroke among the United States dialysis population relative to the general population. Methods We performed a population-based cohort study to compare rates of hospitalized ischemic and hemorrhagic stroke among incident dialysis patients in the United States Renal System database and non-ESRD subjects from the general population identified in the National Hospital Discharge Survey. Results After adjustment for age, gender, and race, estimated rates of hospitalized stroke were markedly higher for dialysis patients compared to the general population. The age-adjusted relative risk (RR) of stroke among dialysis patients compared to the general population was 6.1 [95% Confidence Interval (95% CI) 5.1, 7.1] for Caucasian males, 4.4 (95% CI 3.3, 5.5) for African American males, 9.7 (95%CI 8.2, 11.2) for Caucasians females and 6.2 (95%CI 4.8, 7.6) for African American females. When considered as separate outcomes, hospitalization rates for hemorrhagic and ischemic stroke were both markedly elevated for subjects treated with dialysis (ischemic, RR=4.3 to 10.1; hemorrhagic, RR=4.1 to 6.7). Conclusion Incident dialysis patients are at markedly higher risk for hospitalized stroke when compared to the general population. Although prior public health initiatives have focused primarily on cardiac disease among patients treated with dialysis, our data suggest that new initiatives are needed to control the high risk of stroke in this population.

Studies have shown that protein-energy malnutrition (PEM) is a strong predictor of total mortality among patients with end-stage renal disease (ESRD). The aim of this study is to assess the relationship between nutritional indices and cardiovascular (CV) mortality among patients with ESRD by using data from the US Renal Data System (USRDS) Dialysis Morbidity and Mortality Study Wave I (DMMS-1).Demographic and medical data were abstracted from 5,058 patients who participated in the USRDS DMMS-1. Nutritional measurements of interest included subjective assessment of malnutrition, serum albumin level, body mass index (BMI), and cholesterol level. The USRDS provided follow-up data on mortality through July 1998. The Cox proportional hazard model was used to estimate the risk for CV death associated with nutritional markers.The risk for CV death was 39% greater for each 1-g/dL (10-g/L) decrement in serum albumin level (95% confidence interval [CI], 1.20 to 1.60; P0.001). A care provider's assessment of malnutrition was associated with a 27% greater risk for CV mortality (95% CI, 1.08 to 1.50; P0.004). For each one-unit decrement in BMI, the risk for CV disease (CVD) was 6% greater (95% CI, 1.00 to 1.13; P0.046). Among patients without CVD at the study start, serum albumin level remained a significant risk factor for CV death (adjusted relative risk = 1.39 per 1-g/dL (10-g/L) increment; P = 0.026). In addition, change in albumin levels over time was significantly associated with CV mortality. For each 0.1-g/dL (1-g/L) decrement in albumin level per month, the risk for CV death was 2.24-fold greater (95% CI, 1.65 to 3.02; P0.001) among the entire cohort and 3.86-fold greater (95% CI, 1.96 to 7.60; P0.010) among those without a known history of CVD at the study start.Both PEM at baseline and worsening PEM over time are associated with a greater risk for CV death. This finding persists among dialysis patients without preexisting CVD at baseline.

Hypoalbuminemia and risk of death in pediatric patients with end-stage renal disease. Background Although serum albumin is a marker for malnutrition and associated with a higher mortality in adult patients with end-stage renal disease (ESRD), the risk of death associated with serum albumin is unknown in pediatric patients with ESRD. We evaluated the association between serum albumin and death among pediatric patients initiating dialysis. Methods Data from the United States Renal Data System (USRDS) were used to identify all patients under the age of 18Who initiated dialysis between January 1, 1995 and December 31, 1998. Using the Cox proportional hazards models, the association between serum albumin obtained 45 days prior to dialysis initiation and death was estimated, controlling for demographic factors, dialysis modality, and anthropometric measures. Results Of 1723 patients included in the analysis, there were 93 deaths over 2953 patient-years of observation. The multivariate analysis demonstrated that each -1 g/dL difference in serum albumin between patients was associated with a 54% higher risk of death [adjusted relative risk (aRR), 1.54; 95% confidence interval (CI), 1.15 to 1.85; P = 0.002]. This was independent of glomerular causes for their ESRD and other potential confounding variables. Conclusions Pediatric patients initiating dialysis with hypoalbuminemia are at a higher risk for death. This finding persists after adjusting for glomerular causes for ESRD and other potential confounding variables. Low serum albumin at dialysis initiation is an important marker of mortality risk in pediatric ESRD patients.

c Homocysteine (tHcy) is a risk factor for atherosclerosis in patients with end-stage renal disease and chronic renal insufficiency (CRI). Vitamin B6 deficiency may result in high tHcy levels, especially after a methionine load (PML). Therefore, we evaluated vitamin B6 metabolism and tHcy (fasting and PML) levels in patients with CRI and those on hemodialysis (HD) therapy before and during high-dose sequential vitamin B6 and folic acid supplementation in male patients (27 patients, HD, 17 patients, CRI) and 19 age-matched healthy controls. Vitamin B6 doses were 100 mg/d in patients with CRI and 200 mg/d in HD patients, plus folic acid (5 mg/d), for more than 3 months in each period. We analyzed vitamin B6 metabolites by high-performance liquid chromatography in plasma and red blood cells (RBCs) and fasting tHcy in all cases and PML in subgroups of 11 HD patients and 14 patients with CRI. We found vitamin B6 deficiency and high tHcy (fasting and PML) levels in all patients. Plasma and RBC levels of pyridoxal and pyridoxal phosphate were abnormally low, whereas levels of pyridoxic acid (PA), an end product of vitamin B6 metabolism, were extremely high in both groups. Fasting and PML tHcy levels were partially resistant to vitamin B6 supplements, with different response patterns in HD patients and those with CRI. Thus, the PML defect was more responsive to folic acid in HD patients, whereas vitamin B6 partially reduced PML tHcy levels in patients with CRI. Resistance of tHcy to vitamin B6 treatment in patients with CRI and HD patients is not caused by poor absorption or low tissue stores. Rather, nonvitamin factors or potentially toxic PA levels may be implicated in abnormal vitamin B6 and/or tHcy metabolism during renal insufficiency. © 2002 by the National Kidney Foundation, Inc.

Objective: The study's aim was to evaluate access patency and incidence of revisions in patients initiating hemodialysis and to determine differences in access performance by type of access among patient subgroups. Methods: The study used data from the United States Renal Data System Dialysis Morbidity and Mortality Study Wave 2, which contained a random sample of dialysis patients initiating dialysis in 1996 and early 1997. Failures and revisions were evaluated among 2247 newly placed hemodialysis accesses by using Cox proportional hazards regression model and Poisson regression. Primary and secondary patency rates were estimated using the Kaplan-Meier method. Results: Fifteen hundred seventy-four prosthetic grafts, 492 simple autogenous fistulas, and 181 venous transposition fistulas were available for evaluation. Prosthetic grafts had a 41% greater risk of primary failure compared with simple fistulas (relative risk, 1.41; 95% CI, 1.22-1.64; P